1. Field of the Invention
The present invention relates, in general, to a method of adenovirus mediated transfer of genes to the lung. In particular, the present invention relates to a method of recombinant, replication-deficient adenovirus mediated transfer of desired genes to the lung for the purpose of producing desired proteins of therapeutic or research interest for local or systemic use.
2. Background Information
One of the hurdles to overcome in most forms of somatic gene therapy is the specific delivery of the therapeutic gene (encoding a therapeutic protein) to the organs manifesting the disease. When the lung is the organ to be treated, a functional gene can be delivered directly to the respiratory epithelium by means of tracheal installation. The disadvantage of such an approach is due to the normal biology of the respiratory epithelium; only a small proportion of alveolar and airway epithelial cells go through the proliferative cycle in one day, and a large proportion of the cells are terminally differentiated and are, therefore, incapable of proliferation (Evans, M. J. and Shami, S. G. (1989) In: Lung Cell Biology (C. Lenfant, D. Massaro, Eds.) Marcel Dekker, New York, pp. 1-36). In this regard, it may be difficult to transfer functional genes to the respiratory epithelium by means of vectors (such as retroviruses) that require proliferation of the target cells for expression of the newly transferred gene (Miller, D. G. et al. (1990) Mol. Cell. Biol. 10, 4239).
To circumvent the slow target-cell proliferation, the present invention uses a recombinant adenoviral vector to transfer a recombinant gene to the respiratory epithelium in vivo. Host cell proliferation is not required for expression of adenoviral proteins (Horwitz, M. S. et al. (1990) In: Virology (B. N. Fields and D. M. Knipe, Eds.) Raven Press, New York, ed. 2, pp. 1679-1721 and Berkner, K. L. (1988) Biotechniques 6, 616) and adenoviruses are normally trophic for the respiratory epithelium (Straus, S. E. (1984) In: The Adenoviruses (H. S. Ginsberg Ed.) Plenan Press, New York and London, pp. 451-496).
Other advantages of adenoviruses as potential vectors for human gene therapy are as follows: (i) recombination is rare; (ii) there are no known associations of human malignancies with adenoviral infections despite common human infection with adenoviruses; (iii) the adenovirus genome (which is a linear, double-stranded piece of DNA) can be manipulated to accommodate foreign genes ranging in size from small peptides to up to 7.0 to 7.5 kb in length; and (iv) live adenovirus, having as an essential characteristic the ability to replicate, has been safely used as a human vaccine (Horwitz, M. S. et al. (1990) In: Virology (B. N. Fields and D. M. Knipe, Eds.) Raven Press, New York, ed. 2, pp. 1679-1721; Berkner, K. L. (1988) Biotechniques 6, 616; Straus, S. E. (1984) In: The Adenoviruses (H. S. Ginsberg Ed.) Plenan Press, New York and London, pp. 451-496; Chanock, R. M. et al. (1966) J. Am. Med. Assoc. 195, 151; Haj-Ahmad, Y. and Graham, F. L. (1986) J. Virol. 57, 267; Ballay, A. et al. (1985) EMBO J. 4, 3861).